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Tracing a new treatment for skin cancer to its roots in ICR science

18
Sep
2014

NICE has approved the skin cancer drug dabrafenib for use on the NHS. Much of the work characterising the function of the mutant protein it targets was carried out at the ICR and here we talk about the story of the research behind BRAF inhibitors.

Posted on 18 September, 2014 by Eva Sharpe

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Scanning electron microscope image of a blood vessel in a melanoma
Copyright Wellcome Images

 

Today we received the news that NICE has approved the skin cancer drug dabrafenib for use on the NHS. 

Dabrafenib targets a particular mutation in the BRAF gene found in half of patients with malignant melanoma, and it’s a drug of particular interest to us here at The Institute of Cancer Research.

We didn’t discover dabrafenib, but we did do much of the work to unpick the function of the mutant protein it targets, and I’ve been following its progress through the NICE appraisal processes closely. It’s great to see research done in our laboratories here taken forward and now delivering real benefits for patients.

Dabrafenib is effective in patients who have a specific mutation in a protein called BRAF, which is involved in an important signalling system in cells known as the MAP kinase pathway. In cells with normal BRAF, the MAP kinase pathway can be switched on and off. But in cells with a mutation in BRAF known as V600E, the pathway is constantly switched on, driving the development of cancer.

The BRAF V600E mutation was originally discovered by researchers working at the Wellcome Trust Sanger Institute in Cambridge and here at the ICR in London. In the 1990s, two ICR researchers, Professor Richard Marais and Professor Chris Marshall, were researching oncogenes - genes that cause cancers - and one in particular called RAS. They found that the RAS protein activates BRAF, and predicted that BRAF would play a key part in cancer-causing pathways. They thought it was very likely that mutant BRAF would turn out to be an oncogene too.

Collaborating with Professor Mike Stratton, a former ICR researcher and now the Director of the Sanger Institute, they looked for potential cancer-causing mutations in BRAF. In 1997, they published a crucial paper confirming their theory that BRAF was also an oncogene, and identifying the V600E mutation. The discovery of the mutation – and research linking it to around 50% of aggressive melanomas - prompted a worldwide search for inhibitors of the BRAF protein, as a potentially exciting new approach to cancer treatment.

The ICR continued to work on BRAF, and a team led by Professor David Barford revealed the structure of the mutant protein – a key step in enabling the drug discovery programmes that went on to target it. Dabrafenib was developed commercially, but its discovery relied heavily on the science done here at the ICR.

Our work continues on BRAF and the MAP kinase signalling pathway, and ICR researcher Professor Caroline Springer is searching for drugs which are effective against BRAF and other cancer mutations simultaneously. You can read more about her work in this area on her web pages here.

The approval of dabrafenib, and before it vemurafenib - another melanoma drug accepted for use on the NHS in 2012 – represents a major step forward for patients with melanoma.

Before these drugs came along, there were very few treatment options for patients with advanced melanoma. No one is pretending that these are magic bullets for the disease – most cancers will become resistant to treatment within a year – but both drugs offer patients many months of extra life.

We talk of how the ICR and our partner The Royal Marsden have a bench to bedside approach. Often ICR researchers discover new treatments themselves, work with colleagues at The Royal Marsden to take them into the clinic, and take lessons from the clinical experience back into our research.

Here, some crucial clinical work on BRAF inhibitors was performed at The Royal Marsden, in collaboration with researchers here at the ICR. We may not have discovered dabrafenib, but it’s still an excellent example of our scientific strategy in action – showing how our research can be influential in driving forward exciting new ideas for treatment, and applying those ideas to patients in the clinic.

 

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